large-scale linkage disequilibrium mapping to identify rheumatoid arthritis-associated genes
DESCRIPTION
Large-scale Linkage Disequilibrium Mapping to Identify Rheumatoid Arthritis-associated Genes. Ryo Yamada IMS U of Tokyo Tokyo Japan 1 st International Symposium on Key Issues on Infectious Diseases June 5 2007 Grand Hilton Hotel Seoul Korea. Rheumatoid Arthritis. - PowerPoint PPT PresentationTRANSCRIPT
Large-scale Linkage Disequilibrium Mapping to Identify Rheumatoid
Arthritis-associated Genes
Ryo YamadaIMS U of Tokyo
Tokyo Japan1st International Symposium on Key Issues on Infectious
DiseasesJune 5 2007
Grand Hilton Hotel Seoul Korea
Rheumatoid Arthritis World-wide distribution
with prevalence from 0.6% to 1.0%
Woman-dominant Complex etiology
Genetic components Environmental
components Destructive polyarthritis Extra-articular
involvement Autoimmunity
Genetics and Genetic Analysis of Rheumatoid Arthritis
Twin and family studies Relative risk to monozygotic twin ( λMZ )
12~62
Relative risk to siblings (λsib) 2~17
HLA locus explains 1/3-1/2 of total genetic components.
There are multiple non-HLA genes. Multiple linkage studies Many candidate-approach studies
SNP-based large scale LD-mapping
The first stage From the end of 20th century to 2003 Human genome sequence was being completed SNPs and LD were being characterized High-throughput SNP genotyping platforms were being devel
oped The second stage
From 2003 ~ HapMap project offered variation map for whole-genome st
udy Multiple commercial genotyping packages are available Significant reduction in the typing cost
98
76541 2 3
1 2 3 7698
4 5
Coding Gene-based Approach
Map-based Approach
Gene A Gene B
Gene A Gene B
Gene D
Gene C
Gene C
Gene D
Two Ways of Whole Genome LD Mapping~ First stage ~
SNP distribution of RIKEN study
SNPs
Sam
ples
Replication-based analysisSNPs
Sam
ple
s
Stage 1
Stag
e 2
One-Stage DesignOne-Stage Design
Joint analysisSNPs
Sam
ples Stage 1
Stag
e 2
Two-Stage DesignTwo-Stage Design
Michael Boehnke : Design Considerations in Large Scale Genetic Association Studies
HapMap Tutorials
836 vs. 658 two-stage joint screening
12,890 / 21,153 genes
12,890 ( 60.9% ) genes were evaluated with block/SNPs
No. SNPs per gene and density of SNPs
5.0±6.4 /gene0.2±0.3 /kb
No. coding genes in autosomal chromosomes : 21,153
Covered with SNPs
not in block
Covered with block
Not covered
4,509
8,381
8,263 12,89
0
Gene
20052000 2001
2002 2003 2004
10k20k
40k30k
50k
RIEN project started
27,283Genes
Japanese, Korean :
RA-specific
Caucasians :
SLE RA and other autoimmunities
Japanese : RA
Caucasian : IBD
Japanese :
RA and other autoimmunities
Major findings from SNP-based studies
Major findings from SNP-based studies
Japanese study (RIKEN) PADI4 : RA
Post-translational enzyme to produce targets of the most RA-specific autoantibodies.
SLC22A4 /A5 : RA & Crohn Ergothioneine or carnitine transporter expressed in he
matologic lineages. FCRL3 : RA, SLR & AITD
Fc receptor homolog on B-cell membrane
US study (A.Begovich et al.) PTPN22 : T1DM, SLE, RA & AITD
Lymphoid-specific intracellular phophatase
Validation with meta-analysis
MΦ
Anti-oxydant transporter
Multiple Genes and Multiple Diseases
Summary
Coding gene-based SNP-LD mapping identified multiple RA-susceptible genes with functional variants.
Some genes are associated with multiple autoimmume diseases.
What will change in the next stage of LD-mapping?
SNP markers Genes Genotyping technologies and
further developments SNPs and other polymorphisms Larger study scale and the
associated problems in analysis What are the genetic “association”
studies?
International HapMap Consortium Expands Mapping EffortMap of Human Genetic Variation Will Speed Search for Disease Genes
BETHESDA, Md., Mon., Feb. 7, 2005
Populations CEU CHB+JPN YRI
Total Non-Redundant 3,904,218 3,936,482 3,846,092
Total QC+ SNPs 4,871,127 4,881,441 4,774,448
Total Gentyped SNPs 6,838,923 6,799,238 6,798,546
No. markers is increasing and a chart for LD-mapping is now available.
Genome-scan kits are available.
SNPs
Central Dogma and DNA Variations and their functionality
DNA
mRNA
Peptide
Transcription
Translation
Transcription initiation point
Transcription termination point
Splicing and mRNA maturation
Translation initiation point
Codon triplets
Translation termination point
Variations
Variations
Variations
Variations
Variations
Post-translational peptide modifications
Molecules
Genes
Susceptible Non-susceptible
DNA-mRNA-Protein relation is not straight, but comparison between DNA variations and
phenotype variations bypassing mRNA/proteins simplifies the analysis structure.
Genome
TranscriptomeProteome
Metabolome
Phenome
All-or-non simplest case
Genes
Another big world of heritable items (genes)
Non-coding RNA x 23,000 in mammals
Functional RNA-genes Non-coding genes
Genes
Coding gene
Non-coding-gene
DNAFunctional
RNA
Effects on transcription
Effects on translation
Effects on phenotypes
Genes
Genotyping technologies and further developments
100K marker-panel 250K marker-panel 500K marker-panel …1M marker-panel … … Whole genome typing of all
samples
Typing
Jennifer L. Freeman et al. Genome Res. 2006; 16: 949-961
Other polymorphisms
SNPs CNVs
Biased samplingEven sampling
Sampling from a structured populationLarge study-associated problems
00.10.20.30.40.50.60.70.80.9
1
0.01
0.11
0.21
0.31
0.41
0.51
0.61
0.71
0.81
0.91
Fisher's exact P
パー
セン
タイ
ル 構造化なし
構造化あり、ケースコントロール均質構造化あり、ケースコントロール不均一
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 1 0 1 1 0 0 0 0 1 0 1 0 0 0 0 0 0 1 0 1 1 0 1 0 0 1 1 1 1 1 0 1 0 1 1 0 0 1 0 0 1 1 1 1 0 0 1 1 0 0 0 1 1 0 0 1 00 0 1 0 1 1 1 1 1 0 0 1 0 1 1 1 1 1 0 0 0 1 1 0 0 0 0 1 1 1 0 1 1 1 1 0 0 1 0 0 1 1 0 0 0 0 1 0 1 0 1 0 1 1 0 1 1 11 1 0 0 1 1 1 1 0 0 1 1 1 1 1 1 1 0 0 0 0 0 1 1 0 0 0 0 1 0 1 1 1 0 0 0 1 0 0 1 0 0 1 1 0 0 0 0 1 0 1 0 0 1 1 1 1 01 1 1 1 0 0 1 1 1 1 1 1 1 1 1 0 0 1 1 1 0 0 1 0 1 0 0 1 1 1 0 1 1 0 0 0 1 1 1 0 1 1 0 1 1 0 0 0 1 0 0 0 0 1 0 0 1 01 0 0 0 0 1 0 0 0 0 1 0 1 0 1 0 0 1 0 1 1 1 0 0 1 1 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 1 0 0 1 0 1 1 0 1 1 1 1 0 0 0 1 01 1 1 0 1 1 1 1 1 1 0 1 0 1 0 0 0 1 1 0 1 0 0 1 0 1 0 0 0 1 0 0 0 1 0 0 0 0 0 1 1 1 0 0 1 1 0 1 1 1 0 1 0 1 1 0 0 11 1 0 1 0 1 0 0 1 0 0 1 0 0 1 0 1 0 0 0 1 0 1 0 1 1 0 1 0 0 0 0 0 0 0 1 0 1 1 1 1 0 1 1 0 0 0 1 0 0 1 0 1 1 0 0 0 10 1 0 0 0 0 1 1 1 1 0 0 1 0 0 0 0 1 1 1 1 0 1 0 0 0 1 1 1 0 1 0 0 0 1 1 1 0 0 0 0 0 0 0 1 0 0 0 1 0 0 1 0 1 0 0 1 11 0 1 0 0 0 1 1 1 1 0 0 1 1 0 1 0 1 1 0 0 0 1 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 1 1 0 1 1 0 0 0 1 1 1 1 0 0 0 1 0 1 1 11 1 0 0 1 1 0 1 1 0 0 1 1 0 1 1 1 0 0 1 1 1 1 1 0 1 1 0 0 1 1 0 0 0 0 1 1 1 0 1 0 1 0 0 0 1 1 0 0 1 0 1 0 0 1 0 0 01 0 1 0 0 1 1 0 0 1 0 0 0 1 1 0 1 1 1 0 0 0 0 1 0 1 1 1 0 0 0 0 0 0 0 1 1 0 1 0 0 0 1 0 1 0 1 1 0 1 0 0 0 0 0 0 1 11 1 0 1 1 1 0 0 0 1 0 1 0 1 1 0 1 0 1 1 0 0 0 0 0 1 1 0 1 1 1 0 0 1 0 1 0 0 0 1 1 1 1 1 0 0 1 1 0 0 1 1 1 1 0 1 1 00 1 0 0 1 1 1 0 1 1 0 0 1 1 0 1 0 1 0 0 0 0 0 1 1 0 0 1 0 0 1 0 1 1 1 1 0 1 0 0 0 1 0 1 1 1 0 0 0 0 1 1 0 1 1 1 1 11 1 1 0 0 1 0 0 1 1 0 0 0 0 0 1 0 1 0 0 1 0 0 0 0 0 1 0 0 1 0 0 1 1 1 1 1 1 1 0 1 0 1 1 1 0 1 1 1 0 0 0 1 0 1 0 1 10 1 0 0 1 1 0 1 1 0 0 1 0 0 1 0 1 0 0 0 0 0 1 0 1 0 1 1 1 0 1 1 0 1 0 0 1 0 1 1 1 1 0 0 0 0 1 1 1 0 0 0 0 0 0 1 0 11 1 0 0 0 0 0 0 0 1 1 1 0 0 1 0 0 0 0 0 0 0 1 1 1 0 0 1 1 1 0 1 1 0 0 0 0 0 0 1 1 0 1 0 1 0 0 0 1 0 1 0 1 1 1 1 1 01 1 1 0 0 0 1 0 1 1 0 0 1 0 0 0 0 0 1 0 1 0 0 1 1 0 1 1 1 1 0 1 1 0 1 1 1 1 1 1 1 0 0 1 0 1 0 1 0 0 1 0 0 1 0 1 0 11 1 0 0 0 1 0 1 1 0 1 0 1 0 0 0 1 0 1 1 1 0 1 0 1 0 0 0 0 1 1 0 1 1 0 0 0 0 0 1 1 0 0 0 1 1 1 0 0 0 0 0 1 1 1 1 1 11 0 1 1 0 0 1 0 1 0 1 0 0 1 0 0 1 1 0 1 0 1 1 1 1 0 1 1 0 0 0 0 1 1 0 0 0 1 1 0 1 0 1 1 0 0 0 0 0 1 0 0 1 0 1 0 0 11 1 1 0 0 1 1 1 1 1 1 0 1 0 1 1 1 0 1 0 1 0 0 0 0 1 1 1 0 0 0 1 0 0 1 0 1 1 1 1 1 0 0 1 1 0 0 0 1 1 1 1 1 1 1 1 1 01 0 0 1 1 1 1 0 1 1 0 0 0 1 1 0 0 0 1 1 0 1 0 0 0 1 1 1 1 1 1 1 0 0 0 1 0 1 0 0 0 0 1 1 1 0 0 1 1 1 1 0 0 1 1 1 0 11 0 0 1 0 0 1 0 0 0 0 1 0 0 1 1 0 0 0 1 0 1 1 0 0 0 1 1 0 1 1 0 1 1 0 0 0 1 0 0 0 0 1 0 0 1 0 1 1 1 0 1 1 0 1 1 1 10 1 0 0 0 1 0 1 1 1 0 1 0 1 1 0 1 1 0 0 1 1 0 1 1 0 0 0 0 1 0 1 0 1 1 0 0 0 1 0 0 0 1 0 0 0 1 1 1 0 1 1 1 0 0 0 1 00 1 1 0 0 1 0 0 0 1 1 1 1 1 0 1 1 1 0 0 1 0 1 1 0 0 0 0 1 1 0 0 0 1 1 0 0 0 0 0 0 1 0 1 1 0 1 0 0 1 1 0 0 0 0 0 0 11 1 1 1 0 0 1 0 0 1 1 0 1 0 1 1 0 0 0 1 0 0 1 1 1 0 1 1 1 0 1 0 1 0 1 1 0 1 0 0 0 1 1 0 1 1 0 0 1 0 0 0 1 0 0 0 0 10 0 1 1 1 1 1 0 0 0 1 0 1 1 0 0 1 1 1 1 1 0 0 0 0 1 0 1 1 1 1 0 1 1 1 1 1 1 0 1 0 1 1 1 0 0 0 0 1 0 0 0 0 0 0 1 0 01 0 0 1 1 0 0 0 1 1 0 1 0 0 0 0 0 1 1 1 1 1 0 1 1 1 1 1 1 1 0 0 1 0 1 1 1 1 1 1 0 1 0 1 1 1 0 1 0 1 0 0 1 1 0 0 1 00 1 1 1 0 0 1 0 1 0 1 0 0 1 0 0 0 1 1 0 1 1 0 0 1 0 0 0 1 1 0 0 0 0 0 0 0 0 1 1 0 0 1 1 0 1 1 0 0 0 1 0 0 0 0 0 0 01 0 0 0 1 1 0 1 0 0 1 0 1 1 1 0 1 0 0 0 1 1 0 1 1 0 0 1 1 0 0 1 1 1 0 1 0 1 0 1 0 0 0 0 1 0 1 0 0 1 1 1 1 1 1 1 0 01 1 1 0 0 0 0 0 1 1 1 0 1 1 1 1 0 1 0 1 0 1 1 0 1 0 0 0 1 1 1 0 1 0 0 0 1 1 0 0 1 1 0 0 0 0 0 1 0 1 1 1 1 0 1 1 0 00 0 0 0 1 0 0 0 0 1 0 1 1 1 1 1 1 1 0 1 0 1 1 0 0 0 1 1 0 1 0 1 1 0 0 0 1 1 0 0 1 1 0 0 1 1 1 1 0 1 1 1 0 0 0 1 0 01 1 0 0 1 0 1 0 1 1 1 1 0 0 1 1 0 1 0 1 1 0 0 0 0 0 0 0 0 1 0 1 1 1 1 0 0 0 1 1 0 0 0 0 0 0 0 1 0 1 1 0 0 0 1 1 0 10 0 0 0 1 1 1 0 1 0 0 1 0 1 1 1 0 0 0 0 1 0 1 0 0 1 0 1 1 1 0 1 0 0 0 0 0 0 1 1 0 1 1 0 0 0 0 0 1 0 1 1 0 1 0 0 0 10 1 1 1 0 1 1 1 1 0 0 0 0 1 1 1 1 1 1 1 1 1 0 0 0 1 1 0 1 1 0 1 1 1 0 1 1 0 1 0 0 0 1 0 0 1 0 0 0 1 1 1 0 0 1 0 1 10 1 1 0 1 1 0 0 0 0 1 1 1 1 0 1 1 1 0 0 0 1 0 1 1 0 0 0 1 1 1 0 0 1 1 1 0 1 1 1 1 0 1 1 0 1 0 0 0 0 0 1 0 0 0 1 0 10 0 0 1 0 1 0 1 1 1 1 0 0 1 0 1 1 1 0 1 0 0 0 0 1 1 1 1 0 1 0 1 1 0 0 1 1 0 1 1 1 1 0 0 1 1 1 1 1 1 1 0 0 0 1 0 1 01 0 1 1 0 1 1 0 1 1 1 0 0 1 0 1 1 1 0 1 1 1 0 1 1 0 0 0 0 1 0 1 0 0 1 1 1 0 0 0 0 0 0 1 1 0 1 1 1 0 1 1 0 0 0 1 1 01 1 1 0 1 1 0 0 1 1 1 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 1 0 1 1 1 1 1 1 0 1 1 1 0 0 1 0 0 0 0 1 0 1 1 1 0 11 1 0 1 1 1 0 1 1 0 0 1 0 1 1 0 0 1 1 0 0 0 0 0 0 0 1 0 0 0 0 1 1 0 1 1 1 0 1 1 1 0 0 1 1 0 1 1 1 0 1 1 1 1 1 0 0 11 0 1 1 1 1 0 0 0 0 0 1 1 0 1 1 0 1 0 0 0 0 0 1 0 0 0 0 1 0 1 0 0 1 0 1 1 1 1 0 1 1 0 1 1 1 1 1 0 0 1 0 1 0 0 0 1 10 1 0 0 1 1 0 0 0 1 0 0 0 1 0 0 1 0 1 1 0 1 1 1 1 1 0 1 1 1 0 1 1 1 1 0 1 1 1 0 1 0 1 0 1 0 0 1 0 1 0 0 0 1 1 1 1 00 0 1 0 0 1 1 1 1 1 1 1 1 1 1 0 0 0 0 1 0 0 0 1 0 1 1 1 0 0 0 1 0 1 0 1 0 1 0 1 1 0 0 0 1 1 0 1 0 1 1 1 1 1 1 1 1 00 0 1 1 1 1 1 0 0 1 1 0 1 0 0 1 1 0 1 1 1 1 1 1 0 1 1 0 0 1 0 0 0 0 0 0 1 0 1 0 1 0 1 1 1 0 0 1 0 1 0 0 1 0 1 1 1 00 0 1 0 1 0 0 1 0 0 1 1 0 0 1 1 0 0 1 0 1 1 0 0 0 0 1 0 1 0 1 0 1 0 0 0 1 0 0 1 1 0 0 1 1 1 1 0 0 0 1 1 0 0 1 0 1 00 0 1 1 0 1 1 0 0 1 1 1 1 1 0 1 1 1 0 1 0 1 1 1 0 0 0 0 1 1 0 1 1 0 0 1 1 1 1 0 1 0 1 1 0 1 1 0 0 0 1 0 0 1 1 0 1 00 0 1 1 0 1 1 0 0 1 0 0 0 1 1 0 1 0 1 1 1 1 1 1 0 1 1 0 1 0 1 1 1 0 0 1 0 1 1 0 0 0 1 1 1 0 0 1 0 0 1 0 1 0 0 0 0 10 0 0 1 1 1 1 1 1 1 0 1 0 1 0 0 1 0 1 1 0 0 1 1 1 0 0 1 1 0 1 1 0 1 1 0 0 1 1 1 1 0 0 0 1 0 1 0 0 1 1 1 1 1 0 1 1 01 1 0 1 0 1 0 1 1 1 0 1 1 1 0 1 0 0 0 0 0 0 0 0 0 0 1 0 1 1 0 1 0 0 0 1 1 1 1 1 0 1 0 1 1 1 1 1 1 0 0 1 0 1 0 1 1 01 0 1 0 1 0 1 0 1 0 0 0 0 0 1 1 1 1 1 0 1 1 1 0 0 1 0 1 1 1 0 0 0 0 0 0 0 0 0 1 0 0 0 1 1 1 0 1 0 0 1 1 0 0 0 0 1 11 1 1 1 1 1 1 1 0 0 1 1 0 0 0 0 0 1 1 1 1 0 1 1 1 0 0 1 0 1 0 1 0 0 1 1 1 1 0 0 1 0 0 0 1 0 0 1 1 1 1 1 1 0 1 1 0 10 0 0 0 0 1 0 0 1 0 1 1 0 1 1 1 0 1 0 0 0 1 1 0 1 1 1 1 0 1 0 0 0 0 1 0 0 1 1 1 0 1 1 1 1 0 0 1 0 0 1 1 0 0 1 1 1 00 1 0 0 1 1 1 1 0 1 1 0 1 0 1 1 0 1 0 0 0 0 0 0 1 1 1 0 0 0 1 0 0 1 0 0 1 0 1 0 1 1 1 0 1 0 0 1 0 1 1 0 0 1 1 0 1 10 0 1 1 1 0 0 1 1 0 1 1 0 1 0 1 1 1 0 0 1 1 0 1 0 0 0 0 0 1 0 1 0 1 1 0 1 1 0 0 1 0 1 1 0 0 0 1 0 0 0 0 0 0 0 0 1 00 1 0 1 1 0 0 1 1 0 1 1 0 0 0 1 0 1 1 1 0 1 1 1 0 0 0 1 1 0 0 1 1 1 1 0 0 0 0 0 1 0 0 0 0 1 0 0 0 1 0 0 0 1 0 0 1 10 1 0 0 1 0 0 0 1 0 1 1 1 1 0 1 0 0 1 1 0 1 0 0 1 0 1 1 0 1 1 1 0 0 1 0 0 1 1 1 0 0 1 1 1 1 1 0 0 1 0 0 0 0 1 0 1 01 0 1 0 1 1 0 1 0 1 1 1 1 0 0 0 1 0 0 0 1 1 0 0 1 1 0 1 1 0 0 0 1 0 1 0 0 1 1 0 0 1 0 1 1 1 0 0 0 0 0 0 1 1 0 0 0 11 0 0 0 0 1 0 0 1 0 0 1 1 0 0 0 1 1 0 0 1 0 1 0 0 0 1 0 0 0 0 1 0 1 1 1 0 1 0 1 1 1 0 1 0 0 1 0 0 0 1 1 1 0 0 1 1 10 1 0 0 1 0 0 1 0 0 1 1 1 1 0 0 0 1 1 0 0 0 0 1 0 0 1 1 0 0 0 1 1 1 1 0 1 0 1 1 1 1 1 1 0 1 0 1 1 0 0 1 0 0 0 0 1 11 1 0 0 1 0 0 0 0 0 0 0 1 0 1 1 0 1 0 0 1 1 1 0 0 1 0 1 0 1 1 0 0 0 0 0 1 1 1 1 1 1 1 0 0 0 0 0 0 1 1 0 1 0 1 1 1 10 0 1 1 1 1 0 0 0 0 1 1 1 1 0 0 1 0 0 1 1 1 0 1 0 1 1 1 1 1 0 1 0 0 1 0 1 0 1 1 0 0 1 1 0 0 1 0 1 1 1 0 1 0 1 0 1 01 1 1 1 1 1 0 1 1 0 1 0 1 1 0 1 0 1 0 0 1 1 1 1 1 0 1 1 0 1 0 1 0 1 1 1 1 1 0 1 1 1 1 0 0 1 0 1 0 1 1 1 1 0 1 0 1 1
0 1 0 1 1 0 0 0 0 1 0 1 0 0 0 0 0 0 1 0 1 1 0 1 0 0 1 1 1 1 1 0 1 0 1 1 0 0 1 0 0 1 1 1 1 0 0 1 1 0 0 0 1 1 0 0 1 00 0 1 0 1 1 1 1 1 0 0 1 0 1 1 1 1 1 0 0 0 1 1 0 0 0 0 1 1 1 0 1 1 1 1 0 0 1 0 0 1 1 0 0 0 0 1 0 1 0 1 0 1 1 0 1 1 11 1 0 0 1 1 1 1 0 0 1 1 1 1 1 1 1 0 0 0 0 0 1 1 0 0 0 0 1 0 1 1 1 0 0 0 1 0 0 1 0 0 1 1 0 0 0 0 1 0 1 0 0 1 1 1 1 01 1 1 1 0 0 1 1 1 1 1 1 1 1 1 0 0 1 1 1 0 0 1 0 1 0 0 1 1 1 0 1 1 0 0 0 1 1 1 0 1 1 0 1 1 0 0 0 1 0 0 0 0 1 0 0 1 01 0 0 0 0 1 0 0 0 0 1 0 1 0 1 0 0 1 0 1 1 1 0 0 1 1 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 1 0 0 1 0 1 1 0 1 1 1 1 0 0 0 1 01 1 1 0 1 1 1 1 1 1 0 1 0 1 0 0 0 1 1 0 1 0 0 1 0 1 0 0 0 1 0 0 0 1 0 0 0 0 0 1 1 1 0 0 1 1 0 1 1 1 0 1 0 1 1 0 0 11 1 0 1 0 1 0 0 1 0 0 1 0 0 1 0 1 0 0 0 1 0 1 0 1 1 0 1 0 0 0 0 0 0 0 1 0 1 1 1 1 0 1 1 0 0 0 1 0 0 1 0 1 1 0 0 0 10 1 0 0 0 0 1 1 1 1 0 0 1 0 0 0 0 1 1 1 1 0 1 0 0 0 1 1 1 0 1 0 0 0 1 1 1 0 0 0 0 0 0 0 1 0 0 0 1 0 0 1 0 1 0 0 1 11 0 1 0 0 0 1 1 1 1 0 0 1 1 0 1 0 1 1 0 0 0 1 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 1 1 0 1 1 0 0 0 1 1 1 1 0 0 0 1 0 1 1 11 1 0 0 1 1 0 1 1 0 0 1 1 0 1 1 1 0 0 1 1 1 1 1 0 1 1 0 0 1 1 0 0 0 0 1 1 1 0 1 0 1 0 0 0 1 1 0 0 1 0 1 0 0 1 0 0 01 0 1 0 0 1 1 0 0 1 0 0 0 1 1 0 1 1 1 0 0 0 0 1 0 1 1 1 0 0 0 0 0 0 0 1 1 0 1 0 0 0 1 0 1 0 1 1 0 1 0 0 0 0 0 0 1 11 1 0 1 1 1 0 0 0 1 0 1 0 1 1 0 1 0 1 1 0 0 0 0 0 1 1 0 1 1 1 0 0 1 0 1 0 0 0 1 1 1 1 1 0 0 1 1 0 0 1 1 1 1 0 1 1 00 1 0 0 1 1 1 0 1 1 0 0 1 1 0 1 0 1 0 0 0 0 0 1 1 0 0 1 0 0 1 0 1 1 1 1 0 1 0 0 0 1 0 1 1 1 0 0 0 0 1 1 0 1 1 1 1 11 1 1 0 0 1 0 0 1 1 0 0 0 0 0 1 0 1 0 0 1 0 0 0 0 0 1 0 0 1 0 0 1 1 1 1 1 1 1 0 1 0 1 1 1 0 1 1 1 0 0 0 1 0 1 0 1 10 1 0 0 1 1 0 1 1 0 0 1 0 0 1 0 1 0 0 0 0 0 1 0 1 0 1 1 1 0 1 1 0 1 0 0 1 0 1 1 1 1 0 0 0 0 1 1 1 0 0 0 0 0 0 1 0 11 1 0 0 0 0 0 0 0 1 1 1 0 0 1 0 0 0 0 0 0 0 1 1 1 0 0 1 1 1 0 1 1 0 0 0 0 0 0 1 1 0 1 0 1 0 0 0 1 0 1 0 1 1 1 1 1 01 1 1 0 0 0 1 0 1 1 0 0 1 0 0 0 0 0 1 0 1 0 0 1 1 0 1 1 1 1 0 1 1 0 1 1 1 1 1 1 1 0 0 1 0 1 0 1 0 0 1 0 0 1 0 1 0 11 1 0 0 0 1 0 1 1 0 1 0 1 0 0 0 1 0 1 1 1 0 1 0 1 0 0 0 0 1 1 0 1 1 0 0 0 0 0 1 1 0 0 0 1 1 1 0 0 0 0 0 1 1 1 1 1 11 0 1 1 0 0 1 0 1 0 1 0 0 1 0 0 1 1 0 1 0 1 1 1 1 0 1 1 0 0 0 0 1 1 0 0 0 1 1 0 1 0 1 1 0 0 0 0 0 1 0 0 1 0 1 0 0 11 1 1 0 0 1 1 1 1 1 1 0 1 0 1 1 1 0 1 0 1 0 0 0 0 1 1 1 0 0 0 1 0 0 1 0 1 1 1 1 1 0 0 1 1 0 0 0 1 1 1 1 1 1 1 1 1 01 0 0 1 1 1 1 0 1 1 0 0 0 1 1 0 0 0 1 1 0 1 0 0 0 1 1 1 1 1 1 1 0 0 0 1 0 1 0 0 0 0 1 1 1 0 0 1 1 1 1 0 0 1 1 1 0 11 0 0 1 0 0 1 0 0 0 0 1 0 0 1 1 0 0 0 1 0 1 1 0 0 0 1 1 0 1 1 0 1 1 0 0 0 1 0 0 0 0 1 0 0 1 0 1 1 1 0 1 1 0 1 1 1 10 1 0 0 0 1 0 1 1 1 0 1 0 1 1 0 1 1 0 0 1 1 0 1 1 0 0 0 0 1 0 1 0 1 1 0 0 0 1 0 0 0 1 0 0 0 1 1 1 0 1 1 1 0 0 0 1 00 1 1 0 0 1 0 0 0 1 1 1 1 1 0 1 1 1 0 0 1 0 1 1 0 0 0 0 1 1 0 0 0 1 1 0 0 0 0 0 0 1 0 1 1 0 1 0 0 1 1 0 0 0 0 0 0 11 1 1 1 0 0 1 0 0 1 1 0 1 0 1 1 0 0 0 1 0 0 1 1 1 0 1 1 1 0 1 0 1 0 1 1 0 1 0 0 0 1 1 0 1 1 0 0 1 0 0 0 1 0 0 0 0 10 0 1 1 1 1 1 0 0 0 1 0 1 1 0 0 1 1 1 1 1 0 0 0 0 1 0 1 1 1 1 0 1 1 1 1 1 1 0 1 0 1 1 1 0 0 0 0 1 0 0 0 0 0 0 1 0 01 0 0 1 1 0 0 0 1 1 0 1 0 0 0 0 0 1 1 1 1 1 0 1 1 1 1 1 1 1 0 0 1 0 1 1 1 1 1 1 0 1 0 1 1 1 0 1 0 1 0 0 1 1 0 0 1 00 1 1 1 0 0 1 0 1 0 1 0 0 1 0 0 0 1 1 0 1 1 0 0 1 0 0 0 1 1 0 0 0 0 0 0 0 0 1 1 0 0 1 1 0 1 1 0 0 0 1 0 0 0 0 0 0 01 0 0 0 1 1 0 1 0 0 1 0 1 1 1 0 1 0 0 0 1 1 0 1 1 0 0 1 1 0 0 1 1 1 0 1 0 1 0 1 0 0 0 0 1 0 1 0 0 1 1 1 1 1 1 1 0 01 1 1 0 0 0 0 0 1 1 1 0 1 1 1 1 0 1 0 1 0 1 1 0 1 0 0 0 1 1 1 0 1 0 0 0 1 1 0 0 1 1 0 0 0 0 0 1 0 1 1 1 1 0 1 1 0 00 0 0 0 1 0 0 0 0 1 0 1 1 1 1 1 1 1 0 1 0 1 1 0 0 0 1 1 0 1 0 1 1 0 0 0 1 1 0 0 1 1 0 0 1 1 1 1 0 1 1 1 0 0 0 1 0 01 1 0 0 1 0 1 0 1 1 1 1 0 0 1 1 0 1 0 1 1 0 0 0 0 0 0 0 0 1 0 1 1 1 1 0 0 0 1 1 0 0 0 0 0 0 0 1 0 1 1 0 0 0 1 1 0 10 0 0 0 1 1 1 0 1 0 0 1 0 1 1 1 0 0 0 0 1 0 1 0 0 1 0 1 1 1 0 1 0 0 0 0 0 0 1 1 0 1 1 0 0 0 0 0 1 0 1 1 0 1 0 0 0 10 1 1 1 0 1 1 1 1 0 0 0 0 1 1 1 1 1 1 1 1 1 0 0 0 1 1 0 1 1 0 1 1 1 0 1 1 0 1 0 0 0 1 0 0 1 0 0 0 1 1 1 0 0 1 0 1 10 1 1 0 1 1 0 0 0 0 1 1 1 1 0 1 1 1 0 0 0 1 0 1 1 0 0 0 1 1 1 0 0 1 1 1 0 1 1 1 1 0 1 1 0 1 0 0 0 0 0 1 0 0 0 1 0 10 0 0 1 0 1 0 1 1 1 1 0 0 1 0 1 1 1 0 1 0 0 0 0 1 1 1 1 0 1 0 1 1 0 0 1 1 0 1 1 1 1 0 0 1 1 1 1 1 1 1 0 0 0 1 0 1 01 0 1 1 0 1 1 0 1 1 1 0 0 1 0 1 1 1 0 1 1 1 0 1 1 0 0 0 0 1 0 1 0 0 1 1 1 0 0 0 0 0 0 1 1 0 1 1 1 0 1 1 0 0 0 1 1 01 1 1 0 1 1 0 0 1 1 1 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 1 0 1 1 1 1 1 1 0 1 1 1 0 0 1 0 0 0 0 1 0 1 1 1 0 11 1 0 1 1 1 0 1 1 0 0 1 0 1 1 0 0 1 1 0 0 0 0 0 0 0 1 0 0 0 0 1 1 0 1 1 1 0 1 1 1 0 0 1 1 0 1 1 1 0 1 1 1 1 1 0 0 11 0 1 1 1 1 0 0 0 0 0 1 1 0 1 1 0 1 0 0 0 0 0 1 0 0 0 0 1 0 1 0 0 1 0 1 1 1 1 0 1 1 0 1 1 1 1 1 0 0 1 0 1 0 0 0 1 10 1 0 0 1 1 0 0 0 1 0 0 0 1 0 0 1 0 1 1 0 1 1 1 1 1 0 1 1 1 0 1 1 1 1 0 1 1 1 0 1 0 1 0 1 0 0 1 0 1 0 0 0 1 1 1 1 00 0 1 0 0 1 1 1 1 1 1 1 1 1 1 0 0 0 0 1 0 0 0 1 0 1 1 1 0 0 0 1 0 1 0 1 0 1 0 1 1 0 0 0 1 1 0 1 0 1 1 1 1 1 1 1 1 00 0 1 1 1 1 1 0 0 1 1 0 1 0 0 1 1 0 1 1 1 1 1 1 0 1 1 0 0 1 0 0 0 0 0 0 1 0 1 0 1 0 1 1 1 0 0 1 0 1 0 0 1 0 1 1 1 00 0 1 0 1 0 0 1 0 0 1 1 0 0 1 1 0 0 1 0 1 1 0 0 0 0 1 0 1 0 1 0 1 0 0 0 1 0 0 1 1 0 0 1 1 1 1 0 0 0 1 1 0 0 1 0 1 00 0 1 1 0 1 1 0 0 1 1 1 1 1 0 1 1 1 0 1 0 1 1 1 0 0 0 0 1 1 0 1 1 0 0 1 1 1 1 0 1 0 1 1 0 1 1 0 0 0 1 0 0 1 1 0 1 00 0 1 1 0 1 1 0 0 1 0 0 0 1 1 0 1 0 1 1 1 1 1 1 0 1 1 0 1 0 1 1 1 0 0 1 0 1 1 0 0 0 1 1 1 0 0 1 0 0 1 0 1 0 0 0 0 10 0 0 1 1 1 1 1 1 1 0 1 0 1 0 0 1 0 1 1 0 0 1 1 1 0 0 1 1 0 1 1 0 1 1 0 0 1 1 1 1 0 0 0 1 0 1 0 0 1 1 1 1 1 0 1 1 01 1 0 1 0 1 0 1 1 1 0 1 1 1 0 1 0 0 0 0 0 0 0 0 0 0 1 0 1 1 0 1 0 0 0 1 1 1 1 1 0 1 0 1 1 1 1 1 1 0 0 1 0 1 0 1 1 01 0 1 0 1 0 1 0 1 0 0 0 0 0 1 1 1 1 1 0 1 1 1 0 0 1 0 1 1 1 0 0 0 0 0 0 0 0 0 1 0 0 0 1 1 1 0 1 0 0 1 1 0 0 0 0 1 11 1 1 1 1 1 1 1 0 0 1 1 0 0 0 0 0 1 1 1 1 0 1 1 1 0 0 1 0 1 0 1 0 0 1 1 1 1 0 0 1 0 0 0 1 0 0 1 1 1 1 1 1 0 1 1 0 10 0 0 0 0 1 0 0 1 0 1 1 0 1 1 1 0 1 0 0 0 1 1 0 1 1 1 1 0 1 0 0 0 0 1 0 0 1 1 1 0 1 1 1 1 0 0 1 0 0 1 1 0 0 1 1 1 00 1 0 0 1 1 1 1 0 1 1 0 1 0 1 1 0 1 0 0 0 0 0 0 1 1 1 0 0 0 1 0 0 1 0 0 1 0 1 0 1 1 1 0 1 0 0 1 0 1 1 0 0 1 1 0 1 10 0 1 1 1 0 0 1 1 0 1 1 0 1 0 1 1 1 0 0 1 1 0 1 0 0 0 0 0 1 0 1 0 1 1 0 1 1 0 0 1 0 1 1 0 0 0 1 0 0 0 0 0 0 0 0 1 00 1 0 1 1 0 0 1 1 0 1 1 0 0 0 1 0 1 1 1 0 1 1 1 0 0 0 1 1 0 0 1 1 1 1 0 0 0 0 0 1 0 0 0 0 1 0 0 0 1 0 0 0 1 0 0 1 10 1 0 0 1 0 0 0 1 0 1 1 1 1 0 1 0 0 1 1 0 1 0 0 1 0 1 1 0 1 1 1 0 0 1 0 0 1 1 1 0 0 1 1 1 1 1 0 0 1 0 0 0 0 1 0 1 01 0 1 0 1 1 0 1 0 1 1 1 1 0 0 0 1 0 0 0 1 1 0 0 1 1 0 1 1 0 0 0 1 0 1 0 0 1 1 0 0 1 0 1 1 1 0 0 0 0 0 0 1 1 0 0 0 11 0 0 0 0 1 0 0 1 0 0 1 1 0 0 0 1 1 0 0 1 0 1 0 0 0 1 0 0 0 0 1 0 1 1 1 0 1 0 1 1 1 0 1 0 0 1 0 0 0 1 1 1 0 0 1 1 10 1 0 0 1 0 0 1 0 0 1 1 1 1 0 0 0 1 1 0 0 0 0 1 0 0 1 1 0 0 0 1 1 1 1 0 1 0 1 1 1 1 1 1 0 1 0 1 1 0 0 1 0 0 0 0 1 11 1 0 0 1 0 0 0 0 0 0 0 1 0 1 1 0 1 0 0 1 1 1 0 0 1 0 1 0 1 1 0 0 0 0 0 1 1 1 1 1 1 1 0 0 0 0 0 0 1 1 0 1 0 1 1 1 10 0 1 1 1 1 0 0 0 0 1 1 1 1 0 0 1 0 0 1 1 1 0 1 0 1 1 1 1 1 0 1 0 0 1 0 1 0 1 1 0 0 1 1 0 0 1 0 1 1 1 0 1 0 1 0 1 01 1 1 1 1 1 0 1 1 0 1 0 1 1 0 1 0 1 0 0 1 1 1 1 1 0 1 1 0 1 0 1 0 1 1 1 1 1 0 1 1 1 1 0 0 1 0 1 0 1 1 1 1 0 1 0 1 1
P 値昇順プロット
P 値P-value
Markers
Large study-associated problems
Many significant results when samples are biased with population structure.
Species are distinct categorical phenotypes with many genetic differences.Species-specific genetic factors are difficult to nail down.
Association studies?
Human individuals are unique but phenotypic variations are less distinct than species.Intra-species genetic variations are much less than inter-species, but still difficult to identify association between phenotypic and genetic variations.
Association studies?
Nature Reviews Genetics 3, 380-390 (2002); doi:10.1038/nrg795GENEALOGICAL TREES, COALESCENT THEORY AND THE ANALYSIS OF GENETIC POLYMORPHISMS
Nature Reviews Genetics 3, 380-390 (2002); doi:10.1038/nrg795GENEALOGICAL TREES, COALESCENT THEORY AND THE ANALYSIS OF GENETIC POLYMORPHISMS
Inter-species differences
Intra-species differences
Phylogeny and Ancestral Recombination Graph
Association studies?
Genetic Approach and Molecular Validation
Genetic Approach Dissection of combined effects of multiple
variations in many genes on phenotypes in human.
Molecular Validation Molecular assays to reveal causative links
between genetic variations and phenotype manifestation.
Genetic Validation with Controlled Interventions Transgenic animals are also used for validation
of findings from genetic studies in human.
Lab of Functional Genomics
IMS @ U of Tokyo
Mark Lathrop
Yukinori Okada
Harumi Nagai
Lab for Rheumatic Diseases @ SRC RIKEN
Kazuhiko Yamamoto
Akari Suzuki
Yuta Kochi
Kenichi Shimane
Keiko Myozen
Kyoko Kobayashi
Miyako Ohtake
Emi Kanno
Yoshinobu Hayashi
Keiko Komakine
Yusuke Nakamura
CGM @ Kyoto U
Fumihiko Matsuda
Koichiro Ohmura
Meiko Takahashi
Alexandre Vasilescu
Victor Renault
Masao Yamaguchi
Katsura Hirosawa
Kenei Ohigashi
Akiko Yoshizumi
Miki Kokubo
Shoko Matsubara
Time course
Triggering Event
Disease Manifestations
Diagnosis
Clinical F/UBirth
No observation In pre-clinical phase
RNA, proteins and others DNA
DNA-analyses Data is Simple and Fixed throughout the Life.
No quantitative, chronological or spatial variation is present for DNA polymorphisms.
Time course
Birt
RNA, proteins and others DNA